Balloon angioplasty has been utilized for a number of years to treat coronary arteries narrowed by plaque deposits. A catheter having an inflatable balloon secured to its distal end is advanced through an artery to a narrowed region. The balloon is then inflated with a fluid from an external source, causing the narrowed region of the artery to be expanded. The balloon is then deflated and withdrawn. Other transluminal angioplasty techniques have been proposed, including the use of laser energy to vaporize plaque deposits and the use of a heating element to melt and plow through plaque deposits.
A serious problem associated with angioplasty has been the occurrence in up to 30% of the cases of so-called restenosis, either immediately after the procedure or within six months. Evidence from various studies demonstrates that smooth muscle cell proliferation plays a major role in the intimal hyperplasia that occurs after angioplasty or vascular injury. See, for example, G. E. Austin et al, "Intimal Proliferation of Smooth Muscle Cells as an Explanation for Recurrent Coronary Artery Stenosis After Percutaneous Transluminal Coronary Angioplasty", JACC, Vol. 6, No. 2, Aug. 1985, pages 369-375. Thus, inhibition of smooth muscle cell proliferation is expected to reduce neointima formation and the incidence of restenosis. Proposed techniques for inhibiting smooth muscle cell proliferation have involved administration of heparin and heparin derivatives. See, for example, U.S. Pat. No. 4,824,436 issued Apr. 25, 1989 to Wolinsky and U.S. Pat. No. 5,032,679 issued Jul. 16, 1991 to Brandley et al.
Another technique for inhibiting smooth muscle cell proliferation following vascular recanalization is disclosed in U.S. Pat. No. 5,116,864 issued May 26, 1992 to March et al. A photoactivatable psoralen is administered to a patient prior to a recanalization procedure. After recanalization of a stenosed blood vessel, ultraviolet radiation is delivered to the recanalized region, causing the psoralen to be activated. The activated psoralen reportedly inhibits smooth muscle cell proliferation. The mechanism of the antiproliferative effect is postulated to be due to the formation of psoralen-DNA adducts that impair DNA translation and replication.
The use of ultraviolet radiation for activation of the psoralen has certain disadvantages. The construction of a catheter having an optical fiber and a diffusing tip for delivery of ultraviolet radiation is relatively difficult. Furthermore, the ultraviolet radiation has a relatively shallow penetration depth in the stenosed region of the blood vessel, whereas relatively deep penetration is desired to effectively inhibit smooth muscle cell proliferation. Finally, ultraviolet radiation is known to be mutagenic and cytotoxic when applied to human tissue.
S. Sastry et al, "Recent Advances in the Synthesis and Structure Determination of Site Specifically Psoralen-Modified DNA Oligonucleotides", J. Photochem. Photobiol. B: Biol., Vol. 14, 1992, pages 65-79, describes activation of synthetic psoralen in a DNA solution at 406.7 and 413 nanometers. The synthetic psoralen compound (hydroxymethyl-psoralen) is not approved for clinical use. The DNA solution described by Sastry et al contained a relatively high concentration of the synthetic psoralen.
It is an object of the present invention to provide improved methods for photoactivation of psoralen when used to inhibit smooth muscle cell proliferation.
It is another object of the present invention to provide improved methods for prevention of restenosis following transluminal angioplasty.
It is a further object of the present invention to provide improved methods for inhibition of smooth muscle cell proliferation following transluminal angioplasty.